Certain Substituted Amides, Method of Making, and Method of Use Thereof

ABSTRACT

Compounds of Formula I that inhibit Btk are described herein. Pharmaceutical compositions comprising at least one compound of Formula I, together with at least one pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are described. Methods of treating patients suffering from certain diseases responsive to inhibition of Btk activity and/or B-cell activity are described. Methods for determining the presence of Btk in a sample are described.

Provided herein are certain substituted amides and related compounds,compositions comprising such compounds, and methods of their use.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Bruton's Tyrosine Kinase (Btk) is a member of the Tecfamily of tyrosine kinases, and is a regulator of early B-celldevelopment as well as mature B-cell activation, signaling, andsurvival.

B-cell signaling through the B-cell receptor (BCR) can lead to a widerange of biological outputs, which in turn depend on the developmentalstage of the B-cell. The magnitude and duration of BCR signals must beprecisely regulated. Aberrant BCR-mediated signaling can causedisregulated B-cell activation and/or the formation of pathogenicauto-antibodies leading to multiple autoimmune and/or inflammatorydiseases. Mutation of Btk in humans results in X-linkedagammaglobulinaemia (XLA). This disease is associated with the impairedmaturation of B-cells, diminished immunoglobulin production, compromisedT-cell-independent immune responses and marked attenuation of thesustained calcium sign upon BCR stimulation.

Evidence for the role of Btk in allergic disorders and/or autoimmunedisease and/or inflammatory disease has been established inBtk-deficient mouse models. For example, in standard murine preclinicalmodels of systemic lupus erythematosus (SLE), Btk deficiency has beenshown to result in a marked amelioration of disease progression.Moreover, Btk deficient mice can also be resistant to developingcollagen-induced arthritis and can be less susceptible toStaphylococcus-induced arthritis.

A large body of evidence supports the role of B-cells and the humoralimmune system in the pathogenesis of autoimmune and/or inflammatorydiseases. Protein-based therapeutics (such as Rituxan) developed todeplete B-cells, represent an approach to the treatment of a number ofautoimmune and/or inflammatory diseases. Because of Btk's role in B-cellactivation, inhibitors of Btk can be useful as inhibitors of B-cellmediated pathogenic activity (such as autoantibody production).

Btk is also expressed in osteoclasts, mast cells and monocytes and hasbeen shown to be important for the function of these cells. For example,Btk deficiency in mice is associated with impaired IgE-mediated mastcell activation (marked diminution of TNF-alpha and other inflammatorycytokine release), and Btk deficiency in humans is associated withgreatly reduced TNF-alpha production by activated monocytes.

Thus, inhibition of Btk activity can be useful for the treatment ofallergic disorders and/or autoimmune and/or inflammatory diseases suchas: SLE, rheumatoid arthritis, multiple vasculitides, idiopathicthrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis,and asthma. In addition, Btk has been reported to play a role inapoptosis; thus, inhibition of Btk activity can be useful for cancer, aswell as the treatment of B-cell lymphoma and leukemia. Moreover, giventhe role of Btk in osteoclast function, the inhibition of Btk activitycan be useful for the treatment of bone disorders such as osteoporosis.

Provided is a compound of Formula I:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R₁ is chosen from:

-   R₂ is H or CH₃;-   Z is chosen from phenylene and pyridylidene wherein phenylene and    pyridylidene are optionally substituted with one or more groups    independently chosen from CN, halo, hydroxyl, optionally substituted    lower alkyl, and optionally substituted lower alkoxy;

is chosen from

-   -   each of which is optionally substituted with one or two groups        chosen from hydroxy, cyano, halo, optionally substituted lower        alkyl, and optionally substituted lower alkoxy;

-   each R₁₆ is independently chosen from hydrogen, cyano, optionally    substituted cycloalkyl, and optionally substituted lower alkyl;

-   R₁₇, R₁₈, R₁₉, R₂₁, R₂₂, and R₂₃ are independently chosen from    hydrogen and optionally substituted lower alkyl;

-   each R₂₀ is independently chosen from hydrogen, hydroxy, cyano,    halo, optionally substituted lower alkyl, and optionally substituted    lower alkoxy;

-   D is —NHR₇; and

-   R₇ is chosen from optionally substituted aryl and optionally    substituted heteroaryl.

Provided is a pharmaceutical composition, comprising a compound ofFormula I, together with at least one pharmaceutically acceptablevehicle chosen from carriers, adjuvants, and excipients.

Provided is a packaged pharmaceutical composition, comprising

-   -   a pharmaceutical composition described herein; and    -   instructions for using the composition to treat a patient        suffering from a disease responsive to inhibition of Btk        activity.

Provided is a method for treating a patient having a disease responsiveto inhibition of Btk activity, comprising administering to the patientan effective amount of a compound of Formula I.

Provided is a method for treating a patient having a disease chosen fromcancer, bone disorders, autoimmune diseases, inflammatory diseases,acute inflammatory reactions, and allergic disorders comprisingadministering to the patient an effective amount of a compound ofFormula I.

Provided is a method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of a compound ofFormula I sufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent.

Provided is a method of reducing medication error and enhancingtherapeutic compliance of a patient being treated for a diseaseresponsive to inhibition of Btk activity, the method comprisingproviding a packaged pharmaceutical preparation described herein whereinthe instructions additionally include contraindication and adversereaction information pertaining to the packaged pharmaceuticalcomposition.

Provided is a method for inhibiting ATP hydrolysis, the methodcomprising contacting cells expressing Btk with a compound of Formula Iin an amount sufficient to detectably decrease the level of ATPhydrolysis in vitro.

Provided is a method for determining the presence of Btk in a sample,comprising contacting the sample with a compound of Formula I underconditions that permit detection of Btk activity, detecting a level ofBtk activity in the sample, and therefrom determining the presence orabsence of Btk in the sample.

Provided is a method for inhibiting B-cell activity comprisingcontacting cells expressing Btk with a compound of Formula I in anamount sufficient to detectably decrease B-cell activity in vitro.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or compound or “the” kinase or compound is inclusive of one ormore kinases or compounds.

“*” associated with variable R₁ indicates the point of attachment of R₁to the carbonyl carbon of the group —C(O)N(R₂)—. “*” associated withring W indicates the point of attachment of ring W to Z of the group—Z—N(R₂)C(O)R₁. “*” associated with variable B indicates the point ofattachment of B to L of the group “-L-G”.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having one to fourcarbons.

“Cycloalkyl” indicates a saturated hydrocarbon ring group, having thespecified number of carbon atoms, usually from 3 to 7 ring carbon atoms.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl as well as bridged and caged saturated ringgroups such as norbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. Alkoxy groups will usually have from 1 to6 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refersto alkoxy groups having one to four carbons.

“Mono- and di-alkylcarboxamide” encompasses a group of the formula—(C═O)NR_(a)R_(b) where R_(a) and R_(b) are independently chosen fromhydrogen and alkyl groups of the indicated number of carbon atoms,provided that R_(a) and R_(b) are not both hydrogen.

By “alkylthio” is meant an alkyl group of the indicated number of carbonatoms attached through a sulfur bridge.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant an ester group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus aC₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbonatoms attached through its oxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkylamino groups, wherein the alkyl groups are as defined above and have theindicated number of carbon atoms. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propyl-amino.

“Mono- and di-(alkyl)aminoalkyl” encompasses mono- and di-(alkyl)aminoas defined above linked to an alkyl group.

By “amino(alkyl)” is meant an amino group linked to an alkyl grouphaving the indicated number of carbons. Similarly “hydroxyalkyl” is ahydroxy group linked to an alkyl group.

The term “aminocarbonyl” refers to the group —CONR^(b)R^(c), where

-   -   R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b) and R^(c) taken together with the nitrogen to which they        are bound, form an optionally substituted 5- to 7-membered        nitrogen-containing heterocycloalkyl which optionally includes 1        or 2 additional heteroatoms selected from O, N, and S in the        heterocycloalkyl ring;    -   where each substituted group is independently substituted with        one or more substituents independently selected from C₁-C₄        alkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄        alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl,        —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄        alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl),        —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),        cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H,        —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄        alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.        For example, aryl includes 5- and 6-membered carbocyclic        aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring        containing 1 or more heteroatoms chosen from N, O, and S. For        such fused, bicyclic ring systems wherein only one of the rings        is a carbocyclic aromatic ring, the point of attachment may be        at the carbocyclic aromatic ring or the heterocycloalkyl ring.        Bivalent radicals formed from substituted benzene derivatives        and having the free valences at ring atoms are named as        substituted phenylene radicals. Bivalent radicals derived from        univalent polycyclic hydrocarbon radicals whose names end in        “-yl” by removal of one hydrogen atom from the carbon atom with        the free valence are named by adding “-idene” to the name of the        corresponding univalent radical, e.g., a naphthyl group with two        points of attachment is termed naphthylidene. Aryl, however,        does not encompass or overlap in any way with heteroaryl,        separately defined below. Hence, if one or more carbocyclic        aromatic rings is fused with a heterocycloalkyl aromatic ring,        the resulting ring system is heteroaryl, not aryl, as defined        herein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Haloalkyl” indicates alkyl as defined above having the specified numberof carbon atoms, substituted with 1 or more halogen atoms, up to themaximum allowable number of halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or in certain embodiments, from        1 to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon; and    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or in certain embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.        For example, heteroaryl includes a 5- to 7-membered        heterocycloalkyl, aromatic ring fused to a 5- to 7-membered        cycloalkyl ring. For such fused, bicyclic heteroaryl ring        systems wherein only one of the rings contains one or more        heteroatoms, the point of attachment may be at the        heteroaromatic ring or the cycloalkyl ring. When the total        number of S and O atoms in the heteroaryl group exceeds 1, those        heteroatoms are not adjacent to one another. In certain        embodiments, the total number of S and O atoms in the heteroaryl        group is not more than 2. In certain embodiments, the total        number of S and O atoms in the aromatic heterocycle is not more        than 1. Examples of heteroaryl groups include, but are not        limited to, (as numbered from the linkage position assigned        priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl,        3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl,        2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl,        thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl,        benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl,        indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and        5,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from        univalent heteroaryl radicals whose names end in “-yl” by        removal of one hydrogen atom from the atom with the free valence        are named by adding “-idene” to the name of the corresponding        univalent radical, e.g., a pyridyl group with two points of        attachment is a pyridylidene. Heteroaryl does not encompass or        overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

In the term “heteroarylalkyl,” heteroaryl and alkyl are as definedherein, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, pyridylmethyl, thiophenylmethyl, and(pyrrolyl)1-ethyl.

By “heterocycloalkyl” is meant a single aliphatic ring, usually with 3to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3heteroatoms independently selected from oxygen, sulfur, and nitrogen, aswell as combinations comprising at least one of the foregoingheteroatoms. Suitable heterocycloalkyl groups include, for example (asnumbered from the linkage position assigned priority 1), 2-pyrrolinyl,2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl,4-piperdyl, and 2,5-piperzinyl. Morpholinyl groups are alsocontemplated, including 2-morpholinyl and 3-morpholinyl (numberedwherein the oxygen is assigned priority 1). Substituted heterocycloalkylalso includes ring systems substituted with one or more oxo moieties,such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

“Carbamimidoyl” refers to the group —C(═NH)—NH₂.

“Substituted carbamimidoyl” refers to the group —C(═NR^(e))—NR^(f)R^(g)where R^(e), R^(f), and R^(g) is independently chosen from: hydrogenoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocycloalkyl, provided that at least one ofR^(e), R^(f), and R^(g) is not hydrogen and wherein substituted alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

-   -   —R^(a′), —OR^(b′), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b′), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b′)R^(c′), halo, cyano, nitro, —COR^(b′), —CO₂R^(b′),        —CONR^(b′)R^(c′), —OCOR^(b′), —OCO₂R^(a′), —OCONR^(b′)R^(c′),        —NR^(c′)COR^(b′), —NR^(c′)CO₂R^(a′), —NR^(c′)CONR^(b′)R^(c′),        —CO₂R^(b′), —CONR^(b′)R^(c′), —NR^(c′)COR^(b′), —SOR^(a′),        —SO₂R^(a′), —SO₂NR^(b′)R^(c′), and —NR^(c′)SO₂R^(a′),    -   where R^(a′) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b′) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c′) is independently chosen from hydrogen and optionally        substituted C₁-C₄ alkyl; or    -   R^(b′) and R^(c′), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for cycloalkyl, heterocycloalkyl, or        heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄        alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),        —NHC(O)(phenyl),        —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl),        —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl,        —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄        haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),        —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄        haloalkyl).

The term “sulfanyl” includes the groups: —S-(optionally substituted(C₁-C₆)alkyl), —S-(optionally substituted aryl), —S-(optionallysubstituted heteroaryl), and —S-(optionally substitutedheterocycloalkyl). Hence, sulfanyl includes the group C₁-C₆alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-optionally substituted aryl),—S(O)-optionally substituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl, unless otherwise expressly defined, refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

-   -   —R^(a″), —OR^(b″), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b″), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b″)R^(c″), halo, cyano, nitro, —COR^(b″), —CO₂R^(b″),        —CONR^(b″)R^(c″), —OCOR^(b″), —OCO₂R^(a″), —OCONR^(b″)R^(c″),        —NR^(c″)COR^(b″), —NR^(c″)CO₂R^(a″), —NR^(c″)CONR^(b″)R^(c″),        —CO₂R^(b″), —CONR^(b″)R^(c″), —NR^(c″)COR^(b″), —SOR^(a″),        —SO₂R^(a″), —SO₂NR^(b″)R^(c″), and —NR^(c″)SO₂R^(a″),    -   where R^(a″) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b″) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c″) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b″) and R^(c″), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom:

-   -   —R^(a°), —OR^(b°), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b°), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b°)R^(c°), halo, cyano, nitro, —COR^(b°), —CO₂R^(b°),        —CONR^(b°)R^(c°), —OCOR^(b°), —OCO₂R^(a°), —OCONR^(b°)R^(c°),        —NR^(c°)COR^(b°), —NR^(c°)CO₂R^(a°), —NR^(c°)COCONR^(b°)R^(c°),        —CO₂R^(b°), —CONR^(b°)R^(c°), —NR^(c°)COR^(b°), —SOR^(a°),        —SO₂R^(a°), —SO₂NR^(b°)R^(c°), and —NR^(c°)SO₂R^(a°),    -   where R^(a°) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b°) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c°) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b°) and R^(c°), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

-   -   —R^(a†), —OR^(b†), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b†), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b†)R^(c†), halo, cyano, nitro, —COR^(b†), —CO₂R^(b†),        —CONR^(b†)R^(c†), —OCOR^(b†), —OCO₂R^(a†), —OCONR^(b†)R^(c†),        —NR^(c†)COR^(b†), —NR^(c†)CO₂R^(a†), —NR^(c†)CONR^(b†)R^(c†),        —CO₂R^(b†), —CONR^(b†)R^(c†), —NR^(c†)COR^(b†), —SOR^(a†),        —SO₂R^(a†), —SO₂NR^(b†)R^(c†), and —NR^(c†)SO₂R^(a†),    -   where R^(a†v) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b†) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c†) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b†) and R^(c†), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl). In some        embodiments, a substituted alkoxy group is “polyalkoxy” or        —O-(optionally substituted alkylene)-(optionally substituted        alkoxy), and includes groups such as —OCH₂CH₂OCH₃, and residues        of glycol ethers such as polyethyleneglycol, and        —O(CH₂CH₂O)_(x)CH₃, where x is an integer of 2-20, such as 2-10,        and for example, 2-5. Another substituted alkoxy group is        hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is an integer of        1-10, such as 1-4.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)-O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted refers toalkyl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from:

-   -   —R^(a††), —OR^(b††), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b††), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b††)R^(c††), halo, cyano, nitro, —COR^(b††), —CO₂R^(b††),        —CONR^(b††)R^(c††), —OCOR^(b††), —OCO₂R^(a††),        —OCONR^(b††)R^(c††), —NR^(c††)COR^(b††), —NR^(c††)CO₂R^(a††),        —NR^(c††)CONR^(b††)R^(c††), —CO₂R^(b††), —CONR^(b††)R^(c††),        —NR^(c††)COR^(b††), —SOR^(a††), —SO₂R^(a††),        —SO₂NR^(b††)R^(c††), and —NR^(c††)SO₂R^(a††),    -   where R^(a††) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b††) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c††) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b††) and R^(c††), and the nitrogen to which they are        attached, form an optionally substituted heterocycloalkyl group;        and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: hydroxy,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted acyl, aminocarbonyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedheterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl, provided thatonly one R^(d) may be hydroxyl, and wherein substituted alkyl,cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, for example, up to 3) hydrogen atoms are replacedby a substituent independently chosen from:

-   -   —R^(a‡), —OR^(b‡), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-),        —SR^(b‡), guanidine, guanidine wherein one or more of the        guanidine hydrogens are replaced with a lower-alkyl group,        —NR^(b‡)R^(c‡), halo, cyano, nitro, —COR^(b‡), —CO₂R^(b‡),        —CONR^(b‡)R^(c‡), —OCOR^(b‡), —OCO₂R^(a‡), —OCONR^(b‡)R^(c‡),        —NR^(c‡)COR^(b‡), —NR^(c‡)CO₂R^(a‡), —NR^(c‡)CONR^(b‡)R^(c‡),        —CO₂R^(b‡), —CONR^(b‡)R^(c‡), —NR^(c‡)COR^(b‡), —SOR^(a‡),        —SO₂R^(a‡), —SO₂NR^(b‡)R^(c‡), and —NR^(c‡)SO₂R^(a‡),    -   where R^(a‡) is chosen from optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R^(b‡) is chosen from H, optionally substituted C₁-C₆ alkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; and    -   R^(c‡) is chosen from hydrogen and optionally substituted C₁-C₄        alkyl; or    -   R^(b‡) and R^(c‡), and the nitrogen to which they are attached,        form an optionally substituted heterocycloalkyl group; and    -   where each optionally substituted group is unsubstituted or        independently substituted with one or more, such as one, two, or        three, substituents independently selected from C₁-C₄ alkyl,        aryl, heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-,        C₁-C₄ haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄        alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂,        —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄        alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro,        oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄        alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl),        —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄        alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄        alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄        alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl),        —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄        alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl); and    -   wherein optionally substituted acyl, aminocarbonyl,        alkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

As used herein, “modulation” refers to a change in kinase activity as adirect or indirect response to the presence of compounds describedherein, relative to the activity of the kinase in the absence of thecompound. The change may be an increase in activity or a decrease inactivity, and may be due to the direct interaction of the compound withthe kinase, or due to the interaction of the compound with one or moreother factors that in turn affect kinase activity. For example, thepresence of the compound may, for example, increase or decrease kinaseactivity by directly binding to the kinase, by causing (directly orindirectly) another factor to increase or decrease the kinase activity,or by (directly or indirectly) increasing or decreasing the amount ofkinase present in the cell or organism.

Compounds of Formula I include, but are not limited to, optical isomersof Formula I, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition,compounds include Z- and E- forms (or cis- and trans- forms) ofcompounds with carbon-carbon double bonds. Where compounds exist invarious tautomeric forms, chemical entities of the present inventioninclude all tautomeric forms of the compound. Compounds also includecrystal forms including polymorphs and clathrates.

The present invention includes, but is not limited to, compounds ofFormula I and all pharmaceutically acceptable forms thereof.Pharmaceutically acceptable forms of the compounds recited hereininclude pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof. In certainembodiments, the compounds described herein are in the form ofpharmaceutically acceptable salts. Hence, the terms “compound” and“compounds” also encompass pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures. The terms“compound” and “chemical entity” are used interchangeably herein.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COONwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compound is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of the presentinvention, for example ester or amide derivatives of the compounds ofFormula I. The term “prodrugs” includes any compounds that becomecompounds of Formula I when administered to a patient, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula I.

The term “solvate” refers to the chemical entity formed by theinteraction of a solvent and a compound. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points.

The term “non-covalent complex” refers to the chemical entity formed bythe interaction of a compound and another molecule wherein a covalentbond is not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry (G. C. Pimentel andA. L. McClellan, The Hydrogen Bond, Freeman, San Francisco, 1960; R.Taylor and O. Kennard, “Hydrogen Bond Geometry in Organic Crystals”,Accounts of Chemical Research, 17, pp. 320-326 (1984)).

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In certain embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as ameliorationof symptoms, slowing of disease progression, or prevention of diseasee.g., a therapeutically effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of Btkactivity. In some embodiments, a therapeutically effective amount is anamount sufficient to reduce cancer symptoms, the symptoms of bonedisorders, the symptoms of an allergic disorder, the symptoms of anautoimmune and/or inflammatory disease, or the symptoms of an acuteinflammatory reaction. In some embodiments a therapeutically effectiveamount is an amount sufficient to decrease the number of detectablecancerous cells in an organism, detectably slow, or stop the growth of acancerous tumor. In some embodiments, a therapeutically effective amountis an amount sufficient to shrink a cancerous tumor. In certaincircumstances a patient suffering from cancer may not present symptomsof being affected. In some embodiments, a therapeutically effectiveamount of a compound/chemical entity is an amount sufficient to preventa significant increase or significantly reduce the detectable level ofcancerous cells or cancer markers in the patient's blood, serum, ortissues. In methods described herein for treating allergic disordersand/or autoimmune and/or inflammatory diseases and/or acute inflammatoryreactions, a therapeutically effective amount may also be an amountsufficient, when administered to a patient, to detectably slowprogression of the disease, or prevent the patient to whom thecompound/chemical entity is given from presenting symptoms of theallergic disorders and/or autoimmune and/or inflammatory disease, and/oracute inflammatory response. In certain methods described herein fortreating allergic disorders and/or autoimmune and/or inflammatorydiseases and/or acute inflammatory reactions, a therapeuticallyeffective amount may also be an amount sufficient to produce adetectable decrease in the amount of a marker protein or cell type inthe patient's blood or serum. For example, in some embodiments atherapeutically effective amount is an amount of a compound/chemicalentity described herein sufficient to significantly decrease theactivity of B-cells. In another example, in some embodiments atherapeutically effective amount is an amount of a compound of Formula Isufficient to significantly decrease the number of B-cells. In anotherexample, in some embodiments a therapeutically effective amount is anamount of a compound of Formula I sufficient to decrease the level ofanti-acetylcholine receptor antibody in a patient's blood with thedisease myasthenia gravis.

The term “inhibition” indicates a significant decrease in the baselineactivity of a biological activity or process. “Inhibition of Btkactivity” refers to a decrease in Btk activity as a direct or indirectresponse to the presence of a compound of Formula I, relative to theactivity of Btk in the absence of such compound. The decrease inactivity may be due to the direct interaction of the compound with Btk,or due to the interaction of such compound with one or more otherfactors that in turn affect Btk activity. For example, the presence ofthe compound may decrease Btk activity by directly binding to the Btk,by causing (directly or indirectly) another factor to decrease Btkactivity, or by (directly or indirectly) decreasing the amount of Btkpresent in the cell or organism.

Inhibition of Btk activity also refers to observable inhibition of Btkactivity in a standard biochemical assay for Btk activity, such as theATP hydrolysis assay described below. In some embodiments, a compound ofFormula I has an IC₅₀ value less than or equal to 1 micromolar. In someembodiments, a compound of Formula I has an IC₅₀ value less than orequal to less than 25 nanomolar. In some embodiments, a compound ofFormula I has an IC₅₀ value less than or equal to 5 nanomolar.

“Inhibition of B-cell activity” refers to a decrease in B-cell activityas a direct or indirect response to the presence of a compound ofFormula I, relative to the activity of B-cells in the absence of suchcompound. The decrease in activity may be due to the direct interactionof the compound with Btk or with one or more other factors that in turnaffect B-cell activity.

Inhibition of B-cell activity also refers to observable inhibition ofCD86 expression in a standard assay such as the assay described below.In some embodiments, a compound of Formula I has an IC₅₀ value less thanor equal to 10 micromolar. In some embodiments, a compound of Formula Ihas an IC₅₀ value less than or equal to less than 0.5 micromolar. Insome embodiments, a compound of Formula I has an IC₅₀ value less than orequal to 100 nanomolar.

“B cell activity” also includes activation, redistribution,reorganization, or capping of one or more various B cell membranereceptors, e.g., CD40, CD86, and Toll-like receptors TLRs (in particularTLR4), or membrane-bound immunoglobulins, e.g, IgM, IgG, and IgD. Most Bcells also have membrane receptors for Fc portion of IgG in the form ofeither antigen-antibody complexes or aggregated IgG. B cells also carrymembrane receptors for the activated components of complement, e.g.,C3b, C3d, C4, and Clq. These various membrane receptors andmembrane-bound immunoglobulins have membrane mobility and can undergoredistribution and capping that can initiate signal transduction.

B cell activity also includes the synthesis or production of antibodiesor immunoglobulins. Immunoglobulins are synthesized by the B cell seriesand have common structural features and structural units. Fiveimmunoglobulin classes, i.e., IgG, IgA, IgM, IgD, and IgE, arerecognized on the basis of structural differences of their heavy chainsincluding the amino acid sequence and length of the polypeptide chain.Antibodies to a given antigen may be detected in all or several classesof immunoglobulins or may be restricted to a single class or subclass ofimmunoglobulin. Autoantibodies or autoimmune antibodies may likewisebelong to one or several classes of immunoglobulins. For example,rheumatoid factors (antibodies to IgG) are most often recognized as anIgM immunoglobulin, but can also consist of IgG or IgA.

In addition, B cell activity also is intended to include a series ofevents leading to B cell clonal expansion (proliferation) from precursorB lymphocytes and differentiation into antibody-synthesizing plasmacells which takes place in conjunction with antigen-binding and withcytokine signals from other cells.

“Inhibition of B-cell proliferation” refers to inhibition ofproliferation of abnormal B-cells, such as cancerous B-cells, e.g.lymphoma B-cells and/or inhibition of normal, non-diseased B-cells. Theterm “inhibition of B-cell proliferation” indicates no increase or anysignificant decrease in the number of B-cells, either in vitro or invivo. Thus an inhibition of B-cell proliferation in vitro would be anysignificant decrease in the number of B-cells in an in vitro samplecontacted with a compound of Formula I as compared to a matched samplenot contacted with such compound.

Inhibition of B-cell proliferation also refers to observable inhibitionof B-cell proliferation in a standard thymidine incorporation assay forB-cell proliferation, such as the assay described herein. In someembodiments, a compound of Formula I has an IC₅₀ value less than orequal to 10 micromolar. In some embodiments, a compound of Formula I hasan IC₅₀ value less than or equal to less than 500 nanomolar. In someembodiments, a compound of Formula I has an IC₅₀ value less than orequal to 50 nanomolar.

An “allergy” or “allergic disorder” refers to acquired hypersensitivityto a substance (allergen). Allergic conditions include eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions.

“Asthma” refers to a disorder of the respiratory system characterized byinflammation, narrowing of the airways and increased reactivity of theairways to inhaled agents. Asthma is frequently, although notexclusively associated with atopic or allergic symptoms.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

A “disease responsive to inhibition of Btk activity” is a disease inwhich inhibiting Btk kinase provides a therapeutic benefit such as anamelioration of symptoms, decrease in disease progression, prevention ordelay of disease onset, or inhibition of aberrant activity of certaincell-types (monocytes, osteoclasts, B-cells, mast cells, myeloid cells,basophils, macrophages, neutrophils, and dendritic cells).

“Treatment or treating means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Patient” refers to an animal, such as a mammal, that has been or willbe the object of treatment, observation or experiment. The methods ofthe invention can be useful in both human therapy and veterinaryapplications. In some embodiments, the patient is a mammal; in someembodiments the patient is human; and in some embodiments the patient ischosen from cats and dogs.

Provided is a compound of Formula I:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   R₁ is chosen from:

-   R₂ is H or CH₃;-   Z is chosen from phenylene and pyridylidene wherein is optionally    substituted with one or more groups independently chosen from CN,    halo, hydroxyl, optionally substituted lower alkyl, and optionally    substituted lower alkoxy;

is chosen from

-   -   each of which is optionally substituted with one or two groups        chosen from hydroxy, cyano, halo, optionally substituted lower        alkyl, and optionally substituted lower alkoxy;

-   each R₁₆ is independently chosen from hydrogen, cyano, optionally    substituted cycloalkyl, and optionally substituted lower alkyl;

-   R₁₇, R₁₈, R₁₉, R₂₁, R₂₂, and R₂₃ are independently chosen from    hydrogen and optionally substituted lower alkyl;

-   each R₂₀ is independently chosen from hydrogen, hydroxy, cyano,    halo, optionally substituted lower alkyl, and optionally substituted    lower alkoxy;

-   D is —NHR₇; and

-   R₇ is chosen from optionally substituted aryl and optionally    substituted heteroaryl.

In certain embodiments, R₁ is chosen from:

In certain embodiments, R₁ is chosen from:

In certain embodiments, R₁ is chosen from:

In certain embodiments, R₂ is H. In certain embodiments, R₂ is CH₃.

In certain embodiments, Z is chosen from phenylene and pyridylidenewherein is optionally substituted with one or more groups independentlychosen from CH₃, F, and Cl.

In certain embodiments, D is —N(H)-B-L-G wherein

-   -   B is chosen from optionally substituted phenylene, optionally        substituted pyridylidene, optionally substituted pyrazolyl,        optionally substituted 2-oxo-1,2-dihydropyridinyl,

-   -   wherein    -   * indicates the point of attachment to the group -L-G and the        broken bond

indicates the point of attachment to the —N(H)— group;

-   -   each X₁ is independently chosen from N and CR₃₁;    -   each X₂ is independently chosen from N and CR₃₁; and    -   each X₃ is independently chosen from N and CR₃₁; and wherein no        more than one of X₁, X₂, and X₃ is N,    -   each R₃₀ is independently chosen from hydrogen, hydroxy, cyano,        halo, optionally substituted lower alkyl, and optionally        substituted lower alkoxy;    -   each R₃₁ is independently chosen from hydrogen, hydroxy, cyano,        halo, optionally substituted lower alkyl, and optionally        substituted lower alkoxy;    -   L is chosen from optionally substituted C₀-C₄alkylene,        —O-optionally substituted C₀-C₄alkylene, —(C₀-C₄alkylene)(SO)—,        —(C₀-C₄alkylene)(SO₂)—; and —(C₀-C₄alkylene)(C═O)—; and    -   G is chosen from hydrogen, halo, hydroxy, alkoxy, nitro,        optionally substituted alkyl, optionally substituted amino,        optionally substituted carbamimidoyl, optionally substituted        heterocycloalkyl, optionally substituted cycloalkyl, optionally        substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, B is chosen from ortho-phenylene,meta-phenylene, para-phenylene, ortho-pyridylidene, meta-pyridylidene,para-pyridylidene, pyrazol-4-yl,

In certain embodiments, B is chosen from para-phenylene andmeta-phenylene. In certain embodiments, B is para-phenylene.

In certain embodiments, B is para-pyridylidene. In certain embodiments,B is pyrazol-4-yl.

In certain embodiments, B is chosen from

In certain embodiments, B is

In certain embodiments, B is

In certain embodiments, X₁, X₂ and X₃ are independently CR₃₁. In certainembodiments, X₁, X₂ and X₃ are independently CR₃₁ and each R₃₁ ishydrogen.

In certain embodiments, each R₃₀ is hydrogen.

In certain embodiments, L is chosen from optionally substitutedC₀-C₄alkylene, —O-optionally substituted C₀-C₄alkylene,—(C₀-C₄alkylene)(SO₂)—; and —(C₀-C₄alkylene)(C═O)—. In certainembodiments, L is chosen from a covalent bond, —(C═O)—, —CH₂—,—CH₂(C═O)—, —SO₂— and —CH(CH₃)(C═O)—. In some embodiments, L is chosenfrom —(C═O)—, —CH₂—, —CH₂(C═O)—, —SO₂— and —CH(CH₃)(C═O)—. In someembodiments, L is —(C═O)—. In some embodiments, L is —CH₂—. In someembodiments, L is a covalent bond.

In certain embodiments, G is chosen from hydrogen, hydroxy, C₁-C₆alkoxy,optionally substituted amino, optionally substitutedC₃-C₇heterocycloalkyl, optionally substituted C₃-C₇cycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   hydroxy,    -   —NR₈R₉ wherein R₈ and R₉ are independently chosen from hydrogen,        optionally substituted acyl, and optionally substituted        (C₁-C₆)alkyl; or wherein R₈ and R₉, together with the nitrogen        to which they are bound, form an optionally substituted 5- to        7-membered nitrogen containing heterocycloalkyl which optionally        further includes one or two additional heteroatoms chosen from        N, O, and S;    -   optionally substituted        5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl,    -   lower alkoxy, and    -   1H-tetrazol-5-yl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   hydroxy,    -   N-methylethanolamino,    -   —N(C₁-C₆ alkyl)₂,    -   optionally substituted morpholin-4-yl,    -   optionally substituted piperazin-1-yl,    -   optionally substituted piperazin-2-yl,    -   optionally substituted homopiperazin-1-yl, and    -   optionally substituted cyclopropyl.

In certain embodiments, G is chosen from

-   -   hydrogen,    -   —N(C₁-C₆ alkyl)₂,    -   morpholin-4-yl,    -   4-acyl-piperazin-1-yl,    -   4-lower alkyl-piperazin-1-yl,    -   3-oxo-piperazin-1-yl,    -   3-oxopiperazin-2-yl,    -   homopiperazin-1-yl,    -   4-lower alkyl-homopiperazin-1-yl, and    -   cyclopropyl.

In certain embodiments, L is a covalent bond and G is hydrogen.

Also provided is a compound of Formula II:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein

-   -   X is CR₃ or N;    -   R₃ is chosen from H, CH₃, F and Cl;    -   R₄ is chosen from H, CH₃, F and Cl;    -   R₅ is chosen from H, CH₃, F and Cl;    -   R₆ is chosen from H, CH₃, F and Cl; and

R₁, and R₂ are as described above.

In certain embodiments, R₃ is chosen from CH₃, F and Cl.

In certain embodiments, R₄ is H. In certain embodiments, R₄ is CH₃ or F.

In certain embodiments, R₅ is H. In certain embodiments, R₅ is F or Cl.

In certain embodiments, R₆ is H. In certain embodiments, R₆ is F.

Also provided is a compound of Formula III:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁, R₂, X, R₄, R₅,R₆, R₁₆, R₂₁, R₂₂, B, L and G are as defined above. In certainembodiments, R₂₁ is H. In certain embodiments, R₂₂ is H. In certainembodiments, R₁₆ is H. In certain embodiments, R₁₆ is CH₃.

Also provided is a compound of Formula V:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein U is N or CH; and R₁,R₂, X, R₄, R₅, R₆, R₁₆, R₂₁, R₂₂, L and G are as defined above.

Also provided is a compound of Formula IV:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁, R₂, X, R₄, R₅,R₆, R₁₆, R₂₂, B, L and G are as defined above. In certain embodiments,R₂₂ is H. In certain embodiments, R₁₆ is H. In certain embodiments, R₁₆is CH₃.

Also provided is a compound of Formula VI:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein U is N or CH; and R₁,R₂, X, R₄, R₅, R₆, R₁₆, R₂₂, L and G are as defined above.

In certain embodiments, the compound of Formula I is chosen from

-   N-{3-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,4-difluorophenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-fluoro-6-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   (4S,7R)—N-[3-fluoro-6-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide    (+) isomer;-   (4R,7S)—N-[3-fluoro-6-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide    (−) isomer;-   N-(5-(6-(4-(4-(dimethylamino)piperidin-1-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2,4-difluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-methyl-4-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-chloro-4-methyl-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-fluoro-6-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(4-fluoro-2-methyl-3-(6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-fluoro-6-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   (4R,7S)—N-[2-fluoro-5-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide    (−) isomer;-   (4S,7R)—N-[2-fluoro-5-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide    (+) isomer;-   N-(2,6-difluoro-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-fluoro-2-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-chloro-6-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-fluoro-6-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-fluoro-2-methyl-3-(5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-chloro-3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-chloro-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2,6-difluoro-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-fluoro-2-methyl-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-chloro-6-methyl-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-fluoro-6-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-fluoro-6-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2,6-difluoro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(6-fluoro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-chloro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(3-fluoro-6-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(5-fluoro-6-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-{2-methyl-3-[4-methyl-6-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   3-fluoro-N-[2-methyl-3-(4-methyl-6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{5-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-methyl-3-(1-methyl-5-{[5-(morpholin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-(5-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-[2-methyl-3-(1-methyl-5-{[6-(morpholin-4-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[5-({5-[4-(dimethylamino)piperidin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-methylphenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-methyl-3-(1-methyl-5-{[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{2-methyl-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-methyl-3-(5-{[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{2-methyl-3-[1-methyl-6-oxo-5-({6-[4-(propan-2-yl)piperazin-1-yl]pyridazin-3-yl}amino)-1,6-dihydropyridin-3-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[6-(4-ethylpiperazin-1-yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(3-{6-[(4-{[(2-hydroxyethyl)(methyl)amino]methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[6-(4-hydroxy-4-methylpiperidin-1-yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-methyl-3-(1-methyl-5-{[5-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[2-methyl-3-(1-methyl-5-{[5-(1,4-oxazepan-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   N-(2-fluoro-5-(8-(4-(4-methylpiperazin-1-yl)phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide;-   N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide;-   N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide;    and    pharmaceutically acceptable salts, solvates, chelates, non-covalent    complexes, prodrugs, and mixtures thereof.

The present compounds described herein are potent inhibitors of Btk.While not being bound by any theory, certain compounds have improvedproperties in the form of greater efficacy (as measured by, for example,the inhibition of Btk in whole blood and the inhibition of B-cellactivation in mice).

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, suitable proceduresbeing described, for example, in the reaction scheme and examples below,and in analogous methods known in the art. See, also, U.S. applicationSer. No. 11/371,180, filed Mar. 9, 2006, which is incorporated herein byreference in its entirety. For example, compounds of Formula I withvarious R₁ groups may be made from the following compounds:

-   i.e.,    (4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxylic    acid;-   (4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxylic    acid;-   4,7-ethano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxylic acid;-   5,6-dihydro-4,6-methano-4H-cyclopenta[b]thiophene-2-carboxylic acid;-   (4R,8S)-5,6,7,8-tetrahydro-4,8-methano-8H-cyclohepta[b]thiophene-2-carboxylic    acid;-   (4S,8R)-5,6,7,8-tetrahydro-4,8-methano-8H-cyclohepta[b]thiophene-2-carboxylic    acid;-   (4S,7R)-4,7-methano-4,5,6,7-tetrahydro-indole-2-carboxylic acid;-   (4R,7S)-4,7-methano-4,5,6,7-tetrahydro-indole-2-carboxylic acid;-   (1S,4R)-1,4-methano-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid;-   (1R,4S)-1,4-methano-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid;-   4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid;    and-   4,7-ethano-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylic acid.

In some embodiments, compounds of Formula I are administered as apharmaceutical composition or formulation. Accordingly, the inventionprovides pharmaceutical formulations comprising a compound of Formula Iand pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Pharmaceutically acceptable vehicles must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the animal being treated. The vehicle can be inert or it can possesspharmaceutical benefits. The amount of vehicle employed in conjunctionwith the compound is sufficient to provide a practical quantity ofmaterial for administration per unit dose of the compound.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such as sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the compoundof the present invention.

Effective concentrations of a compound of Formula I and pharmaceuticallyacceptable salts, solvates, chelates, non-covalent complexes, prodrugs,and mixtures thereof, are mixed with a suitable pharmaceuticalacceptable vehicle. In instances in which the compound exhibitsinsufficient solubility, methods for solubilizing compounds may be used.Such methods are known to those of skill in this art, and include, butare not limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate.

Upon mixing or addition of the compound of Formula I, the resultingmixture may be a solution, suspension, emulsion or the like. The form ofthe resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe chosen vehicle. The effective concentration sufficient forameliorating the symptoms of the disease treated may be empiricallydetermined.

Compounds of Formula I may be administered orally, topically,parenterally, intravenously, by intramuscular injection, by inhalationor spray, sublingually, transdermally, via buccal administration,rectally, as an ophthalmic solution, or by other means, in dosage unitformulations.

Dosage formulations suitable for oral use, include, for example,tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations. In some embodiments, oral formulations contain from 0.1 to99% of a compound of Formula I. In some embodiments, oral formulationscontain at least 5% (weight %) of a compound of Formula I. Someembodiments contain from 25% to 50% or from 5% to 75% of a compound ofFormula I.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol, or sucrose. Such formulations may also contain ademulcent.

Compounds of Formula I can be incorporated into oral liquid preparationssuch as aqueous or oily suspensions, solutions, emulsions, syrups, orelixirs, for example. Moreover, formulations containing these chemicalentities can be presented as a dry product for constitution with wateror other suitable vehicle before use. Such liquid preparations cancontain conventional additives, such as suspending agents (e.g.,sorbitol syrup, methyl cellulose, glucose/sugar, syrup, gelatin,hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel,and hydrogenated edible fats), emulsifying agents (e.g., lecithin,sorbitan monoleate, or acacia), non-aqueous vehicles, which can includeedible oils (e.g., almond oil, fractionated coconut oil, silyl esters,propylene glycol and ethyl alcohol), and preservatives (e.g., methyl orpropyl p-hydroxybenzoate and sorbic acid).

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; naturally-occurring phosphatides, forexample, lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets typically comprise conventional pharmaceutically acceptableadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmellose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, can beuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the compound is releasedin the gastrointestinal tract in the vicinity of the desired topicalapplication, or at various times to extend the desired action. Suchdosage forms typically include, but are not limited to, one or more ofcellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes andshellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable vehicle, for example asa solution in 1,3-butanediol. Among the acceptable vehicles that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can be useful in the preparation ofinjectables.

Compounds of Formula I may be administered parenterally in a sterilemedium. Parenteral administration includes subcutaneous injections,intravenous, intramuscular, intrathecal injection or infusiontechniques. Compounds of Formula I, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle. In many compositionsfor parenteral administration the carrier comprises at least 90% byweight of the total composition. In some embodiments, the carrier forparenteral administration is chosen from propylene glycol, ethyl oleate,pyrrolidone, ethanol, and sesame oil.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient that is solid at ordinary temperatures but liquid at rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycols.

Compounds of Formula I may be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye. Topical compositions may be in any formincluding, for example, solutions, creams, ointments, gels, lotions,milks, cleansers, moisturizers, sprays, skin patches, and the like.

Such solutions may be formulated as 0.01%-10% isotonic solutions, pH5-7, with appropriate salts. Compounds of Formula I may also beformulated for transdermal administration as a transdermal patch.

Topical compositions comprising a compound of Formula I can be admixedwith a variety of carrier materials well known in the art, such as, forexample, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin Aand E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate,and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Representative emollients include stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate,iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, andmyristyl myristate; propellants, such as propane, butane, iso-butane,dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such asethyl alcohol, methylene chloride, iso-propanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide,tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, andgelatin; and powders, such as chalk, talc, fullers earth, kaolin,starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites, trialkyl aryl ammonium smectites, chemicallymodified magnesium aluminium silicate, organically modifiedmontmorillonite clay, hydrated aluminium silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethyleneglycol monostearate.

Compounds of Formula I may also be topically administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine and phosphatidylcholines.

Other compositions useful for attaining systemic delivery of thecompound include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhance or beindependent of therapeutic effects of the present compounds. Particularclasses of activity enhancers include skin penetration enhancers andabsorption enhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents that can be chosen from a wide variety of molecules, whichcan function in different ways to enhance the therapeutic effects of acompound of Formula I. These optional other active agents, when present,are typically employed in the compositions of the invention at a levelranging from 0.01% to 15%. Some embodiments contain from 0.1% to 10% byweight of the composition. Other embodiments contain from 0.5% to 5% byweight of the composition.

The invention includes packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition comprising acompound of Formula I and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures thereof, andinstructions for using the composition to treat a mammal (typically ahuman patient). In some embodiments, the instructions are for using thepharmaceutical composition to treat a patient suffering from a diseaseresponsive to inhibition of Btk activity and/or inhibition of B-celland/or myeloid-cell activity. The invention can include providingprescribing information; for example, to a patient or health careprovider, or as a label in a packaged pharmaceutical formulation.Prescribing information may include for example efficacy, dosage andadministration, contraindication and adverse reaction informationpertaining to the pharmaceutical formulation.

In all of the foregoing the compounds of Formula I can be administeredalone, as mixtures, or in combination with other active agents.

Accordingly, the invention includes a method of treating a patient, forexample, a mammal, such as a human, having a disease responsive toinhibition of Btk activity, comprising administrating to the patienthaving such a disease, an effective amount of a compound of Formula Iand pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.

To the extent that Btk is implicated in disease, alleviation of thedisease, disease symptoms, preventative, and prophylactic treatment iswithin the scope of this invention. In some embodiments, compounds ofFormula I may also inhibit other kinases, such that alleviation ofdisease, disease symptoms, preventative, and prophylactic treatment ofconditions associated with these kinases is also within the scope ofthis invention.

Methods of treatment also include inhibiting Btk activity and/orinhibiting B-cell and/or myeloid-cell activity, by inhibiting ATPbinding or hydrolysis by Btk or by some other mechanism, in vivo, in apatient suffering from a disease responsive to inhibition of Btkactivity, by administering an effective concentration of a compound ofFormula I and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof. An example of aneffective concentration would be that concentration sufficient toinhibit Btk activity in vitro. An effective concentration may beascertained experimentally, for example by assaying blood concentrationof the compound, or theoretically, by calculating bioavailability.

In some embodiments, the condition responsive to inhibition of Btkactivity and/or B-cell and/or myeloid-cell activity is cancer, a bonedisorder, an allergic disorder and/or an autoimmune and/or inflammatorydisease, and/or an acute inflammatory reaction.

The invention includes a method of treating a patient having cancer, abone disorder, an allergic disorder and/or an autoimmune and/orinflammatory disease, and/or an acute inflammatory reaction, byadministering an effective amount of a compound of Formula I andpharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.

In some embodiments, the conditions and diseases that can be affectedusing compounds of Formula I, include, but are not limited to:

allergic disorders, including but not limited to eczema, allergicrhinitis or coryza, hay fever, bronchial asthma, urticaria (hives) andfood allergies, and other atopic conditions;autoimmune and/or inflammatory diseases, including but not limited topsoriasis, Crohn's disease, irritable bowel syndrome, Sjogren's disease,tissue graft rejection, and hyperacute rejection of transplanted organs,asthma, systemic lupus erythematosus (and associatedglomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma,vasculitis (ANCA-associated and other vasculitides), autoimmunehemolytic and thrombocytopenic states, Goodpasture's syndrome (andassociated glomerulonephritis and pulmonary hemorrhage),atherosclerosis, rheumatoid arthritis, osteoarthritis, chronicIdiopathic thrombocytopenic purpura (ITP), Addison's disease,Parkinson's disease, Alzheimer's disease, Diabetes mellitus (type 1),septic shock, myasthenia gravis, Ulcerative Colitis, Aplastic anemia,Coeliac disease, Wegener's granulomatosis and other diseases in whichthe cells and antibodies arise from and are directed against theindividual's own tissues;acute inflammatory reactions, including but not limited to skin sunburn,inflammatory pelvic disease, inflammatory bowel disease, urethritis,uvitis, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, and cholocystitis,cancer, including but not limited to hematological malignancies, such asB-cell lymphoma, and acute lymphoblastic leukemia, acute myelogenousleukemia, chronic myelogenous leukemia, chronic and acute lymphocyticleukemia, hairy cell leukemia, Hodgkin's disease, Non-Hodgkin lymphoma,multiple myeloma, and other diseases that are characterized by cancer ofthe blood or lymphatic system,andbone disorders, including but not limited to osteoporosis.

Btk is a known inhibitor of apoptosis in lymphoma B-cells. Defectiveapoptosis contributes to the pathogenesis and drug resistance of humanleukemias and lymphomas. Thus, further provided is a method of promotingor inducing apoptosis in cells expressing Btk comprising contacting thecell with a compound of Formula I, pharmaceutically acceptable salts,solvates, chelates, non-covalent complexes, prodrugs, and mixturesthereof.

The invention provides methods of treatment in which a compound ofFormula I, and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof, is the onlyactive agent given to a patient and also includes methods of treatmentin which a compound of Formula I, and pharmaceutically acceptable salts,solvates, chelates, non-covalent complexes, prodrugs, and mixturesthereof, is given to a patient in combination with one or moreadditional active agents.

Thus in one embodiment the invention provides a method of treatingcancer, a bone disorder, an allergic disorder and/or an autoimmuneand/or inflammatory disease, and/or an acute inflammatory reaction,which comprises administering to a patient in need thereof an effectiveamount of a compound of Formula I and pharmaceutically acceptable salts,solvates, chelates, non-covalent complexes, prodrugs, and mixturesthereof, together with a second active agent, which can be useful fortreating a cancer, a bone disorder, an allergic disorder and/or anautoimmune and/or inflammatory disease, and/or an acute inflammatoryreaction. For example the second agent may be an anti-inflammatoryagent. Treatment with the second active agent may be prior to,concomitant with, or following treatment with a compound of Formula Iand pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof. In certain embodiments, acompound of Formula I and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, prodrugs, and mixtures thereof, iscombined with another active agent in a single dosage form. Suitableantitumor therapeutics that may be used in combination with a compoundof Formula I include, but are not limited to, chemotherapeutic agents,for example mitomycin C, carboplatin, taxol, cisplatin, paclitaxel,etoposide, doxorubicin, or a combination comprising at least one of theforegoing chemotherapeutic agents. Radiotherapeutic antitumor agents mayalso be used, alone or in combination with chemotherapeutic agents.

Compounds of Formula I can be useful as chemosensitizing agents, and,thus, can be useful in combination with other chemotherapeutic drugs, inparticular, drugs that induce apoptosis.

A method for increasing sensitivity of cancer cells to chemotherapy,comprising administering to a patient undergoing chemotherapy achemotherapeutic agent together with a compound of Formula I andpharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, in an amount sufficient toincrease the sensitivity of cancer cells to the chemotherapeutic agentis also provided herein.

Examples of other chemotherapeutic drugs that can be used in combinationwith the present compounds include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines), tyrosine kinaseinhibitors (e.g., Gleevac), and the like.

Included herein are methods of treatment in which a compound of FormulaI and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, prodrugs, and mixtures thereof, is administeredin combination with an anti-inflammatory agent. Anti-inflammatory agentsinclude but are not limited to NSAIDs, non-specific and COX-2 specificcyclooxygenase enzyme inhibitors, gold compounds, corticosteroids,methotrexate, tumor necrosis factor receptor (TNF) receptorsantagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate.Salicylates include but are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be chosen from cortisone, dexamethasone,methylprednisolone, prednisolone, prednisolone sodium phosphate, andprednisone.

In additional embodiments the anti-inflammatory therapeutic agent is agold compound such as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, infliximab, and adalimumab (Humira®) which are anti-TNFalpha monoclonal antibodies.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asmethotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, ormycophenolate mofetil.

Still other embodiments of the invention pertain to combinations withRituxan® (Rituximab) or other agents that work by selectively depletingCD20+ B-cells.

Dosage levels of the order, for example, of from 0.1 mg to 140 mg perkilogram of body weight per day can be useful in the treatment of theabove-indicated conditions (0.5 mg to 7 g per patient per day). Theamount of active ingredient that may be combined with the vehicle toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. Dosage unit forms willgenerally contain from 1 mg to 500 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In some embodiments, for example, for thetreatment of an allergic disorder and/or autoimmune and/or inflammatorydisease, a dosage regimen of 4 times daily or less is used. In someembodiments, a dosage regimen of 1 or 2 times daily is used. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination and the severity of the particular diseasein the patient undergoing therapy.

A labeled form of a compound of the invention can be used as adiagnostic for identifying and/or obtaining compounds that have thefunction of modulating an activity of a kinase as described herein. Thecompounds of the invention may additionally be used for validating,optimizing, and standardizing bioassays.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophene-2-carboxamide(1q)

3-Chlorobicyclo[2.2.1]hept-2-ene-2-carbaldehyde (1b)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged withanhydrous 1,2-dichloroethane (24 mL) and anhydrous DMF (9.12 g, 125mmol). The reaction mixture was cooled to 0° C., and phosphorusoxychloride (15.3 g, 100 mmol) was added over 5 min, while maintainingthe reaction temperature between 0 and 10° C. The cooling bath wasremoved, and the reaction was stirred at room temperature for 30 min. Asolution of 1a (5.50 g, 50.0 mmol) in 1,2-dichloroethane (10 mL) wasadded, and the mixture was heated at 80° C. overnight. After this time,the reaction was poured into a solution of potassiummonohydrogenphosphate (43.5 g, 250 mmol) in water (200 mL) and stirredfor 15 min. The organic layer was separated and concentrated underreduced pressure. The residue was dissolved in hexanes (100 mL) andwashed with water (2×100 mL). The hexanes layer was dried over sodiumsulfate, filtered and loaded on a plug of a 15-40 μM silica gel (150mL). The compound was eluted with a gradient from 0% to 3% of ethylacetate in hexanes, and the fractions containing 1b were collected toafford, after concentrating under reduced pressure, a 29% yield (2.23 g)of 1b as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 9.80 (s, 1H), 3.42 (s,1H), 3.07 (d, 1H, J=1.7 Hz), 1.95-1.77 (m, 2H), 1.67 (dt, 1H, J=8.9, 1.8Hz), 1.41-1.17 (m, 3H).

Ethyl 4,5,6,7-Tetrahydro-4,7-methanobenzo[b]thiophene-2-carboxylate (1d)

A 50-mL three-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was purged with nitrogen and charged with 1b (1.00g, 6.41 mmol), chloroform (20 mL), 1c (770 mg, 6.45 mmol) andtriethylamine (1.31 g, 13.0 mmol), and the mixture was stirred at roomtemperature for 3 h and then heated at 60° C. overnight. The resultingsolution was concentrated under reduced pressure. The residue wasdissolved in ethanol (20 mL), and triethylamine (365 mg, 3.61 mmol) wasadded. After heating the reaction mixture at reflux for 4 d, the solventwas evaporated under reduced pressure, and the resulting residue waspartitioned between water (20 mL) and ethyl acetate (20 mL). The layerswere separated, and the aqueous phase was extracted with ethyl acetate(20 mL). The organic extracts were combined, dried over sodium sulfate,filtered and the solvent removed under reduced pressure. The resultingresidue was eluted with a 3% solution of ethyl acetate in hexanes, andthe fractions containing 1d were collected to afford, afterconcentrating under reduced pressure, a 66% yield (934 mg) of 1d as ayellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.53 (s, 1H), 4.30 (q, 2H, J=7.0Hz), 3.55 (m, 1H), 3.42 (m, 1H), 1.97-1.86 (m, 3H), 1.64 (dt, 1H, J=9.0,1.5 Hz), 1.35 (t, 3H, J=7.0 Hz), 1.09 (m, 2H); MS (ESI+) m/z 223.1(M+H).

4,5,6,7-Tetrahydro-4,7-methanobenzo[b]thiophene-2-carboxylic Acid (1e)

A 100-mL single-neck round bottomed flask equipped with a magneticstirrer and reflux condenser was purged with nitrogen and charged with1d (930 mg, 4.19 mmol), ethanol (7 mL), THF (7 mL), water (7 mL) andlithium hydroxide (301 mg, 12.6 mmol) and the mixture heated at 50° C.for 4 h. After this time, the reaction was cooled to room temperatureand acidified to pH 1.5 with 2N hydrochloric acid. The resultingprecipitate was collected by vacuum filtration, washed with water (2×10mL) and dried overnight under vacuum to afford a 94% yield (768 mg) of1e as a white solid: mp 183-184° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.66(br s, 1H), 7.48 (s, 1H), 3.59 (m, 1H), 3.41 (m, 1H), 1.97-1.83 (m, 3H),1.61 (dt, 1H, J=9.0, 2.5 Hz), 0.96 (dd, 2H, J=12.5, 3.5 Hz); MS (APCI−)m/z 193.2 (M−H).

Methyl 2-(4-Nitrophenyl)acetate (1g)

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was charged with 2-(4-nitrophenyl)acetic acid (1f)(14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentratedsulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heatedat reflux for 16 h. After this time, the reaction was concentrated todryness under reduced pressure. The resulting residue was partitionedbetween water (500 mL) and diethyl ether (200 mL) and the layersseparated. The aqueous phase was extracted with diethyl ether (100 mL).The combined organic phases were washed with saturated aqueous sodiumcarbonate and dried over magnesium sulfate, and the drying agent wasremoved by filtration. The filtrate was concentrated under reducedpressure and dried to a constant weight under vacuum to afford a 96%yield of 1g (14.6 g) as a white solid: mp 45-46° C.; ¹H NMR (500 MHz,CDCl₃) δ8.19 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H),3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.

Methyl 2-Bromo-2-(4-nitrophenyl)acetate (1 h)

A 1-L single-neck round-bottomed flask equipped with a magnetic stirrerand reflux condenser was charged with 1g (10.6 g, 54.1 mmol), carbontetrachloride (120 mL), N-bromosuccinimide (10.7 g, 59.9 mmol) andazobisisobutylonitrile (275 mg, 1.67 mmol), and the reaction mixture washeated at reflux for 18 h. After this time the reaction was cooled toroom temperature and poured into heptane (120 mL). The resultingsuspension was filtered and the filter cake washed with heptane (40 mL).The filtrate was concentrated under reduced pressure and the resultingresidue was subjected to flash chromatography to afford 1h in 72% yield(10.7 g) as a clear oil: ¹H NMR (500 MHz, CDCl₃) δ8.23 (d, 2H, J=9 Hz),7.74 (d, 2H, J=9.0 Hz), 5.40 (s, 1H), 3.82 (s, 3H); MS (ESI−) m/z 272(M−H). Reference: Tetrahedron 2002, 58, 10113.

1,4-Dimethyl-3-(4-nitrophenyl)piperazin-2-one (1j)

A 100-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen, charged withN¹,N²-dimethylethane-1,2-diamine (1i) (1.61 g, 18.2 mmol), ethanol (5mL) and 1h (500 mg, 1.82 mmol), and the reaction was stirred at roomtemperature for 1 h. After this time, the reaction mixture wasevaporated under reduced pressure, and the resulting residue waspurified by flash column chromatography to afford an 89% yield (404 mg)of 1j as a yellow oil: ¹H NMR (500 MHz, DMSO-d₆) δ 8.18 (d, 2H, J=8.5Hz), 7.60 (d, 2H, J=8.5 Hz), 3.87 (s, 1H), 3.61 (td, 1H, J=12.0, 4.0Hz), 3.26 (ddd, 1H, J=12.0, 4.0, 2.5 Hz), 3.02 (ddd, 1H, J=12.0, 4.0,2.5 Hz), 2.84 (s, 3H), 2.64 (td, 1H, J=12.0, 4.0 Hz), 2.06 (s, 3H).

3-(4-Aminophenyl)-1,4-dimethylpiperazin-2-one (1k)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 1j (200 mg, 0.80mmol), ethanol (5 mL) and 10% palladium on carbon (50% wet, 4 mg dryweight). The reaction flask was purged with hydrogen gas and thereaction mixture stirred under a balloon pressure of hydrogen for 2 h.After this time the flask was purged with nitrogen. The catalyst wasremoved by filtration through a pad of Celite 521 and the filter cakewashed with ethanol (10 mL). The filtrate was concentrated under reducedpressure to afford a 94% yield of 1k (166 mg) as a colorless oil: ¹H NMR(500 MHz, DMSO-d₆) δ 6.89 (d, 2H, J=8.5 Hz), 6.47 (d, 2H, J=8.5 Hz),4.94 (s, 2H), 3.53 (td, 1H, J=12.0, 4.0 Hz), 3.44 (m, 1H), 3.21 (dt, 1H,J=12.0, 4.0 Hz), 2.92 (dt, 1H, J=12.0, 4.0 Hz), 2.82 (s, 3H), 2.02 (s,3H); MS (ESI+) m/z 220 (M+H).

3,5-dibromo-1-methyl-2(1H)pyrazinone (1l)

(J. Heterocycl. Chem. 1983, 20, 919)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer and reflux condenser was charged with 1,2-dichlorobenzene (100mL) and oxalyl bromide (60.6 g; 281 mmol). To the solution was addedmethylamino-acetonitrile (7.01 g; 65.8 mmol) and the reaction heatedunder nitrogen to 80° C. After 18 h the resulting mixture was cooled toroom temperature, evaporated under reduced pressure and the resultingresidue purified by flash chromatography to afford3,5-dibromo-1-methyl-2(1H)pyrazinone (1l) (2.87 g, 16%) as an off-whitesolid: mp 94-95° C.; MS (ESI+) m/z 267 (M+H).

5-Bromo-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one(1m)

A 100-mL three-neck round-bottomed flask equipped with a mechanicalstirrer and reflux condenser was charged with 1k (780 mg, 3.56 mmol), 1l(998 mg, 3.73 mmol), cesium carbonate (2.36 g, 7.26 mmol) and1,4-dioxane (40 mL). After bubbling nitrogen through the resultingsolution for 30 minutes, Xantphos (0.162 g, 0.281 mmol) andtris(dibenzylideneacetone)dipalladium(0) (0.15 g, 0.165 mmol) wereadded, and the reaction mixture was heated at reflux for 16 h. Afterthis time the reaction was cooled to room temperature and concentratedunder reduced pressure. The resulting residue was absorbed onto silicagel and purified by flash chromatography to afford a 57% yield (818 mg)of 1m as an orange solid: mp 206-207° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.27(bs, 1H), 7.72 (dd, 1H, J=2.0, 8.5 Hz), 7.36 (dd, 2H, J=2.0, 8.5 Hz),6.73 (s, 1H), 3.71 (m, 1H), 3.69 (s, 1H), 3.52 (s, 3H), 3.21 (m, 1H),3.01 (m, 1H), 2.97 (s, 3H), 2.67 (m, 1H), 2.19 (s, 3H); MS (ESI+) m/z406 (M+H).

4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane(1n)

A 1-L three-neck round-bottomed flask equipped with a mechanical stirrerand thermoregulator was purged with nitrogen and charged with2-bromo-6-nitrotoluene (60.2 g; 278 mmol), bis(pinacolato)diboron (85.2g; 336 mmol), potassium acetate (82.4 g; 840 mmol) and DMSO (320 mL). Astream of nitrogen was passed through the resulting suspension for 30min, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II),complex with dichloromethane (1:1) (7.60 g; 9.30 mmol) was then addedand the reaction heated at 85° C. for 20 h. After this time the mixturewas cooled to ambient temperature, poured into a mixture of water (1300mL) and MtBE (500 mL) and treated with Cellpure P65 (150 cc). Theresulting suspension was filtered through a pad of Cellpure P65 (200 cc)packed onto a fritted funnel (ID 185 mm). The filter cake was washedwith MtBE (3×180 mL) and the organic layer of the filtrate separated,washed with water (3×1 L) and dried over sodium sulfate. After filteringoff sodium sulfate, the filtrate was concentrated and purified by flashchromatography to afford4,4,5,5-tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane(1n) as a light yellow solid: mp 52-53° C.; MS (APCI+) m/z 264 (M+H).

2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1o)

A 500-mL round-bottomed flask equipped with a magnetic stirrer wascharged with4,4,5,5-Tetramethyl-2-(2-methyl-3-nitro-phenyl)-[1,3,2]dioxaborolane(1n) (8.44 g; 32.1 mmol) and methanol (150 mL). The reaction flask wastwice evacuated and back-filled with argon. 10% Palladium on charcoal(50% wet, 425 mg dry weight) was then added to the solution, and thereaction flask evacuated and back-filled with hydrogen three times. Thereaction was then stirred under balloon pressure of hydrogen at roomtemperature for 13 h. After this time, the flask was twice evacuated andback-filled with argon, then filtered through a pad of Celite 521 andthe filtrate concentrated in vacuo. The resulting residue was driedunder high vacuum for 1 d to afford a quantitative yield (8.16 g) of2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1o) as a white solid: mp 110-112° C.; MS (ESI+) m/z 234 (M+H).

5-(3-Amino-2-methylphenyl)-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one(1p)

A 250-mL three-neck round-bottomed flask equipped with a magneticstirrer, reflux condenser and nitrogen inlet was charged with 1m (2.50g, 6.16 mmol), 1o (1.79 g, 7.70 mmol), 1,4-dioxane (70 mL) and asolution of sodium carbonate (1.96 g, 18.5 mmol) in water (14 mL). Afterbubbling nitrogen through the resulting mixture for 30 min,tetrakis(triphenylphosphine)palladium (711 mg, 0.62 mmol) was added andthe reaction mixture then heated at reflux for 11 h. After this time thereaction was cooled to room temperature and 2N hydrochloric acid (70 mL)followed by ethyl acetate (70 mL) was added. The mixture was stirred for0.5 h and then filtered through a pad of Celite 521. The organic layerof the filtrate was separated and extracted with 2N hydrochloric acid(2×30 mL). The acidic extracts were combined and washed with ethylacetate (4×50 mL). The aqueous solution was then stirred vigorously withethyl acetate (100 mL) while solid potassium carbonate was addedportionwise until a pH of 12 was reached. The aqueous layer wasseparated and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine (70 mL) and dried over magnesiumsulfate. The drying agent was removed by filtration, and the filtratewas concentrated under reduced pressure and dried in a 49° C. vacuumoven for 24 h to afford 1p in 86% yield (2.32 g) as an amber foam: mp133-134° C. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (s, 1H), 7.80 (d, 1H, J=8.5Hz), 7.29 (d, 2H, J=8.5 Hz), 7.05 (t, 1H, J=8.0 Hz), 6.79 (d, 1H, J=7.5Hz), 6.73 (d, 1H, J=7.5 Hz), 6.68 (s, 1H), 3.72 (s, 3H), 3.64 (m, 1H),3.20 (m, 1H), 3.01 (m, 1H), 2.99 (s, 3H), 2.66 (m, 1H), 2.24 (s, 3H),2.17 (s, 3H); MS (ESI+) m/z 433.3 (M+H).

N-(3-(6-(4-(1,4-Dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydro-4,7-methanobenzo[b]thiophene-2-carboxamide(1q)

A 50-mL single-neck round-bottomed flask equipped with a magneticstirrer was purged with nitrogen and charged with 1e (100 mg, 0.515mmol), 1p (203 mg, 0.469 mmol), N,N-diisopropylethylamine (242 mg, 1.88mmol) and anhydrous DMF (2 mL).Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 249 mg, 0.563 mmol) was added, and the reaction was heated at 60°C. for 16 h. After this time, the reaction was diluted with water (10mL), and the resulting suspension was filtered. The filter cake wasdissolved in methylene chloride (20 mL), and the solution was washedwith 10% aqueous citric acid (10 mL), saturated aqueous sodiumbicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate.The drying agent was removed by filtration, and the solvent wasevaporated under reduced pressure. The resulting residue was eluted witha gradient from 0% to 20% of methanol in ethyl acetate, and thefractions containing 1q were collected to afford, after concentratingunder reduced pressure, a 44% yield (127 mg) of 1q as an off-whitesolid: mp 178-179° C.; ¹H NMR (500 MHz, CD₂Cl₂) δ 8.35 (s, 1H), 7.85 (d,1H, J=8.0 Hz), 7.77 (d, 2H, J=8.5 Hz), 7.59 (s, 1H), 7.42 (s, 1H),7.29-7.22 (m, 4H), 6.76 (s, 1H), 3.68 (td, 1H, J=11.5, 4.5 Hz),3.62-3.60 (m, 2H), 3.58 (s, 3H), 3.47 (m, 1H), 3.18 (m, 1H), 2.97 (m,1H), 2.91 (s, 3H), 2.64 (m, 1H), 2.39 (s, 3H), 2.13 (s, 3H), 1.98-1.90(m, 3H), 1.67 (dt, 1H, J=9.0, 2.5 Hz), 1.10 (dd, 2H, J=12.5, 3.5 Hz); MS(ESI+) m/z 609.3 (M+H).

EXAMPLE 2

The following compounds were prepared using procedures similar to thosedescribed in Example 1.

MH+ MW m/z Structure Name calc obs

N-[2-fluoro-5-(1-methy1-5- {[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide 584 585.3

(4S,7R)-N-[3-fluoro-6-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridin-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7- methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide (+) isomer 585 586.3

(4R,7S)-N-[3-fluoro-6-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridin-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7- methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide (−) isomer 585 586.3

(4R,7S)-N-[2-fluoro-5-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridin-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (−) isomer 584 585.3

(4S,7R)-N-[2-fluoro-5-(1- methyl-5-{[5-(4- methylpiperazin-1-yl)pyridin-2-yl]amino}-6- oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (+) isomer 584 585.3

EXAMPLE 3

The following compounds can be prepared using procedures similar tothose described in Example 1 and those known in the art.

Structure Name

N-{3-[6-({4-[(2S)-1,4-dimethyl-3- oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7- tetrahydro-1-benzothiophene-2- carboxamide

N-{3-[6-({4-[(2R)-1,4-dimethyl-3- oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-{3-[6-({4-[(2S)-1,4-dimethyl-3- oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-{3-[6-({4-[(2R)-1,4-dimethyl-3- oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-[3-(5-{[5-(4-ethylpiperazin-1- yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)- 2,4-difluorophenyl]-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-(5-(6-(4-(4- (dimethylamino)piperidin-1-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2,4-difluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-methyl-4-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-chloro-4-methyl-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(5-fluoro-6-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2- yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(4-fluoro-2-methyl-3-(6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-fluoro-6-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2- yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-fluoro-2-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(2-chloro-6-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2- ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(5-fluoro-6-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(6-fluoro-2-methyl-3-(5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(5-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6- difluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2- methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-chloro-3-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2- yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-(6-(1-ethyl-1H-pyrazol-4- ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2- yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(5-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(3-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl)-4,7-methano- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide

N-(3-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-chloro-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-(6-(1H-pyrazol-4-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(1- methylpiperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(1-methyl-5-(6-(1- methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2,6-difluoro-3-(1-meth-5-(6-(1- methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-fluoro-2-meth-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-chloro-6-methyl-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-fluoro-6-(1-methyl-5-(6-(1- methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(5-fluoro-6-(1-methyl-5-(6-(1- methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(2-fluoro-5-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2,6-difluoro-3-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-(6-fluoro-3-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-chloro-3-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-6-methylphenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-(3-fluoro-6-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-(5-fluoro-6-(6-(4- ((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-{2-methyl-3-[4-methyl-6-({4-[(4- methylpiperazin-1-yl)carbonyl]phenyl}amino)-5-oxo-4,5- dihydropyrazin-2-yl]phenyl}-4,7-N-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

3-fluoro-N-[2-methyl-3-(4-methyl-6- {[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5- dihydropyrazin-2-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-(3-{5-[(5-cyclopropyl-1H-pyrazol-3- yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-2-methylphenyl)- 4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide

N-[2-methyl-3-(1-methyl-5-{[5- (morpholin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]- 4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide

N-[3-(5-{[5-(4-hydroxy-4- methylpiperidin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-(3-(5-(5- ((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-methylphenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2- carboxamide

N-[2-methyl-3-(1-methyl-5-{[6- (morpholin-4-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]- 4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide

N-{3-[5-([5-[4- (dimethylamino)piperidin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6- dihydropyridin-3-yl]-2-methylphenyl}-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2- carboxamide

N-[2-methyl-3-(1-methyl-5-{[6-(4- methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-[3-(5-{[5-(4-ethylpiperazin-1- yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2- methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-{2-methyl-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)-1,6-dihydropyridin-3- yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-[2-methyl-3-(5-{[6-(4- methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-{2-methyl-3-[1-methyl-6-oxo-5-({6- [4-(propan-2-yl)piperazin-1-yl]pyridazin-3-yl}amino)-1,6- dihydropyridin-3-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-[3-(5-{[6-(4-ethylpiperazin-1- yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2- methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-(3-{6-[(4-{[(2- hydroxyethyl)(methyl)aminolmethyl}phenyl)amino]-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl}-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-[3-(5-{[6-(4-hydroxy-4- methylpiperidin-1-yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

N-[2-methyl-3-(1-methyl-5-{[5-[4- methyl-1,4-diazepan-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3- yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-[2-methyl-3-(1-methyl-5-{[5-(1,4- oxazepan-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]- 4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide

N-{3-[6-(1H-indazol-5-ylamino)-4- methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,7-methano-4,5,6,7- tetrahydro-1-benzothiophene-2-carboxamide

N-[3-(5-{[5-(4-ethylpiperazin-1- yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2- methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2- carboxamide

N-(2-fluoro-5-(8-(4-(4-methylpiperazin- 1-yl)phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(2-(4-(4-methylpiperazin- 1-yl)phenylamino)pyrimidin-4-yl)phenyl)-4,7-methano-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide

N-(2-fluoro-5-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide

N-(2-fluoro-5-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 4,7-ethano-4,5,6,7-tetrahydrobenzo[d]thiazole-2- carboxamide

N-(2-fluoro-5-(1-methyl-5-(5-(4- methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3- yl)phenyl)-5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide

N-(2-fluoro-5-(4-methyl-6-(4-(4- methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)- 5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide

EXAMPLE 4 Biochemical Btk Assay

A generalized procedure for one standard biochemical Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

A master mix minus Btk enzyme is prepared containing 1× Cell Signalingkinase buffer (25 mM Tris-HCl, pH 7.5, 5 mM beta-glycerophosphate, 2 mMdithiothreitol, 0.1 mM Na₃VO₄, 10 mM MgCl₂), 0.5 μM Promega PTKBiotinylated peptide substrate 2, and 0.01% BSA. A master mix plus Btkenzyme is prepared containing 1× Cell Signaling kinase buffer, 0.5 μMPTK Biotinylated peptide substrate 2, 0.01% BSA, and 100 ng/well (0.06mU/well) Btk enzyme. Btk enzyme is prepared as follows: full lengthhuman wildtype Btk (accession number NM-000061) with a C-terminal V5 and6×His tag was subcloned into pFastBac vector for making baculoviruscarrying this epitope-tagged Btk. Generation of baculovirus is donebased on Invitrogen's instructions detailed in its published protocol“Bac-toBac Baculovirus Expression Systems” (Cat. Nos. 10359-016 and10608-016). Passage 3 virus is used to infect Sf9 cells to overexpressthe recombinant Btk protein. The Btk protein is then purified tohomogeneity using Ni-NTA column. The purity of the final proteinpreparation is greater than 95% based on the sensitive Sypro-Rubystaining. A solution of 200 μM ATP is prepared in water and adjusted topH7.4 with 1N NaOH. A quantity of 1.25 μL of compounds in 5% DMSO istransferred to a 96-well ½ area Costar polystyrene plate Compounds aretested singly and with an 11-point dose-responsive curve (startingconcentration is 10 μM; 1:2 dilution). A quantity of 18.75 μL of mastermix minus enzyme (as a negative control) and master mix plus enzyme istransferred to appropriate wells in 96-well ½ area costar polystyreneplate. 5 μL of 200 μM ATP is added to that mixture in the 96-well ½ areaCostar polystyrene plate for final ATP concentration of 40 μM. Thereaction is allowed to incubate for 1 hour at room temperature. Thereaction is stopped with Perkin Elmer 1× detection buffer containing 30mM EDTA, 20 nM SA-APC, and 1 nM PT66 Ab. The plate is read usingtime-resolved fluorescence with a Perkin Elmer Envision using excitationfilter 330 nm, emission filter 665 nm, and 2^(nd) emission filter 615nm. IC₅₀ values are subsequently calculated. Alternatively, theLanthascreen assay can be used to evaluate Btk activity throughquantification of its phosphorylated peptide product. The FRET thatoccurs between the flourescein on the peptide product and the terbium onthe detection antibody decreases with the addition of inhibitors of Btkthat reduce the phosphorylation of the peptide. In a final reactionvolume of 25 uL, Btk (h) (0.1 ng/25 ul reaction) is incubated with 50 mMHepes pH 7.5, 10 mM MgCl₂, 2 mM MnCl₂, 2 mM DTT, 0.2 mM NaVO4, 0.01%BSA, and 0.4 uM fluorescein poly-GAT. The reaction is initiated by theaddition of ATP to 25 uM (Km of ATP). After incubation for 60 minutes atroom temperature, the reaction is stopped by the addition of a finalconcentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30minutes at room temperature. Detection is determined on a Perkin ElmerEnvision with 340 nM excitation and emission at 495 and 520 nm.

EXAMPLE 5 Ramos Cell Btk Assay

Another generalized procedure for a standard cellular Btk Kinase Assaythat can be used to test compounds disclosed in this application is asfollows.

Ramos cells are incubated at a density of 0.5×10⁷ cells/ml in thepresence of test compound for 1 hr at 37° C. Cells are then stimulatedby incubating with 10 μg/ml anti-human IgM F(ab)₂ for 5 minutes at 37°C. Cells are pelleted, lysed, and a protein assay is performed on thecleared lysate. Equal protein amounts of each sample are subject toSDS-PAGE and western blotting with either anti-phosphoBtk (Tyr223)antibody (Cell Signaling Technology #3531) or phosphoBtk (Tyr551)antibody (BD Transduction Labs #558034) to assess Btkautophosphorylation or an anti-Btk antibody (BD Transduction Labs#611116) to control for total amounts of Btk in each lysate.

EXAMPLE 6 B-Cell Proliferation Assay

A generalized procedure for a standard cellular B-cell proliferationassay that can be used to test compounds disclosed in this applicationis as follows.

B-cells are purified from spleens of 8-16 week old Balb/c mice using aB-cell isolation kit (Miltenyi Biotech, Cat # 130-090-862). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic B-cells for 30 min prior to addition of 10 μg/ml of ananti-mouse IgM antibody (Southern Biotechnology Associates Cat #1022-01) in a final volume of 100 μl. Following 24 hr incubation, 1 μCi³H-thymidine is added and plates are incubated an additional 36 hr priorto harvest using the manufacturer's protocol for SPA[³H] thymidineuptake assay system (Amersham Biosciences # RPNQ 0130). SPA-bead basedfluorescence is counted in a microbeta counter (Wallace Triplex 1450,Perkin Elmer).

EXAMPLE 7 T Cell Proliferation Assay

A generalized procedure for a standard T cell proliferation assay thatcan be used to test compounds disclosed in this application is asfollows.

T cells are purified from spleens of 8-16 week old Balb/c mice using aPan T cell isolation kit (Miltenyi Biotech, Cat # 130-090-861). Testingcompounds are diluted in 0.25% DMSO and incubated with 2.5×10⁵ purifiedmouse splenic T cells in a final volume of 100 μl in flat clear bottomplates precoated for 90 min at 37° C. with 10 μg/ml each of anti-CD3 (BD# 553057) and anti-CD28 (BD # 553294) antibodies. Following 24 hrincubation, 1 μCi ³H-thymidine is added and plates incubated anadditional 36 hr prior to harvest using the manufacturer's protocol forSPA[³H] thymidine uptake assay system (Amersham Biosciences # RPNQ0130). SPA-bead based fluorescence was counted in a microbeta counter(Wallace Triplex 1450, Perkin Elmer).

EXAMPLE 8 CD86 Inhibition Assay

A generalized procedure for a standard assay for the inhibition of Bcell activity that can be used to test compounds disclosed in thisapplication is as follows.

Total mouse splenocytes are purified from spleens of 8-16 week oldBalb/c mice by red blood cell lysis (BD Pharmingen #555899). Testingcompounds are diluted to 0.5% DMSO and incubated with 1.25×10⁶splenocytes in a final volume of 200 μl in flat clear bottom plates(Falcon 353072) for 60 min at 37° C. Cells are then stimulated with theaddition of 15 μ[g/ml IgM (Jackson ImmunoResearch 115-006-020), andincubated for 24 hr at 37° C., 5% CO₂. Following the 24 hr incubation,cells are transferred to conical bottom clear 96-well plates andpelleted by centrifugation at 1200×g×5 min. Cells are preblocked byCD16/CD32 (BD Pharmingen #553142), followed by triple staining withCD19-FITC (BD Pharmingen #553785), CD86-PE (BD Pharmingen #553692), and7AAD (BD Pharmingen #51-68981E). Cells are sorted on a BD FACSCaliburand gated on the CD19⁺/7AAD⁻ population. The levels of CD86 surfaceexpression on the gated population is measured versus test compoundconcentration.

EXAMPLE 9 B-ALL Cell Survival Assay

The following is a procedure for a standard B-ALL cell survival studyusing an XTT readout to measure the number of viable cells. This assaycan be used to test compounds disclosed in this application for theirability to inhibit the survival of B-ALL cells in culture. One humanB-cell acute lymphoblastic leukemia line that can be used is SUP-B15, ahuman Pre-B-cell ALL line that is available from the ATCC.

SUP-B15 pre-B-ALL cells are plated in multiple 96-well microtiter platesin 100 μl of Iscove's media+20% FBS at a concentration of 5×10⁵cells/ml. Test compounds are then added with a final conc. of 0.4% DMSO.Cells are incubated at 37° C. with 5% CO₂ for up to 3 days. After 3 dayscells are split 1:3 into fresh 96-well plates containing the testcompound and allowed to grow up to an additional 3 days. After each 24 hperiod, 50 ul of an XTT solution (Roche) is added to one of thereplicate 96-well plates and absorbance readings are taken at 2, 4 and20 hours following manufacturer's directions. The reading taken with anOD for DMSO only treated cells within the linear range of the assay(0.5-1.5) is then taken and the percentage of viable cells in thecompound treated wells are measured versus the DMSO only treated cells.

EXAMPLE 10

The compounds disclosed in the examples above are tested in the Btkbiochemical assay described herein (Example 4) and certain of thosecompounds exhibit an IC₅₀ value less than or equal to 1 micromolar.Certain of those compounds exhibit an IC₅₀ value less than or equal to25 nM. Certain of those compounds exhibit an IC₅₀ value less than orequal to 5 nM.

Some of the compounds disclosed in the examples above are tested in theB-cell proliferation assay (as described in Example 6) and exhibit anIC₅₀ value less than or equal to 10 micromolar. Certain of thosecompounds exhibit an IC₅₀ value less than or equal to 500 nM. Certain ofthose compounds exhibit an IC₅₀ value less than or equal to 50 nM inthis assay.

Certain of those compounds do not inhibit T-cell proliferation and haveIC₅₀ values greater than or equal to 5 micromolar when they are assayedunder conditions described herein (as described in Example 7).

Certain compounds disclosed herein exhibit IC₅₀ values for inhibition ofT-cell proliferation that are at least 3-fold, and in some instances10-fold, or even 100-fold greater than the IC₅₀ values of thosecompounds for inhibition of B-cell proliferation.

Some of the compounds disclosed herein are tested in an assay forinhibition of B cell activity (under the conditions described in Example8), and exhibit an IC₅₀ value less than or equal to 10 micromolar.Certain of those compounds exhibit an IC₅₀ value less than or equal to0.5 micromolar. Certain of those compounds exhibit an IC₅₀ value lessthan or equal to 100 nM in this assay.

Some of the compounds disclosed herein are tested in a B-cell leukemiacell survival assay (under the conditions described in Example 9), andexhibit an IC₅₀ value less than or equal to 10 micromolar.

Some of the compounds disclosed herein exhibit both biochemical andcell-based activity. For example, some of the compounds disclosed hereinexhibit an IC₅₀ value less than or equal to 1 micromolar in the Btkbiochemical assay described herein (Example 4) and an IC₅₀ value lessthan or equal to 10 micromolar in at least one of the cell-based assays(other than the T-cell assay) described herein (Examples 7, 8, 10 or11). Certain of those compounds exhibit an IC₅₀ value less than or equalto 50 nM in the Btk biochemical assay described herein (Example 4) andan IC₅₀ value less than or equal to 500 nM in at least one of thecell-based assays (other than the T-cell assay) described herein(Examples 7, 8, 10 or 11). Certain of those compounds exhibit an IC₅₀value less than or equal to 10 nM and an IC₅₀ value less than or equalto 100 nM in at least one of the cell-based assays (other than theT-cell assay) described herein (Examples 7, 8, 10 or 11).

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

1. A compound of Formula I:

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof, wherein R₁ is chosen from:

R₂ is H or CH₃; Z is chosen from phenylene and pyridylidene whereinphenylene and pyridylidene are optionally substituted with one or moregroups independently chosen from CN, halo, hydroxyl, optionallysubstituted lower alkyl, and optionally substituted lower alkoxy;

is chosen from

each of which is optionally substituted with one or two groups chosenfrom hydroxy, cyano, halo, optionally substituted lower alkyl, andoptionally substituted lower alkoxy; each R₁₆ is independently chosenfrom hydrogen, cyano, optionally substituted cycloalkyl, and optionallysubstituted lower alkyl; R₁₇, R₁₈, R₁₉, R₂₁, R₂₂, and R₂₃ areindependently chosen from hydrogen and optionally substituted loweralkyl; each R₂₀ is independently chosen from hydrogen, hydroxy, cyano,halo, optionally substituted lower alkyl, and optionally substitutedlower alkoxy; D is —NHR₇; and R₇ is chosen from optionally substitutedaryl and optionally substituted heteroaryl.
 2. The compound of claim 1wherein R₁ is chosen


3. The compound of claim 2 wherein the compound is of Formula II,wherein:

X is CR₃ or N; R₃ is chosen from H, CH₃, F and Cl; R₄ is chosen from H,CH₃, F and Cl; R₅ is chosen from H, CH₃, F and Cl; and R₆ is chosen fromH, CH₃, F and Cl.
 4. The compound of claim 3 wherein the compound is ofFormula III:


5. The compound of claim 4 wherein the compound is of Formula V, whereinU is N or CH:


6. The compound of claim 3 wherein the compound is of Formula IV:


7. The compound of claim 6 wherein the compound is of Formula VI,wherein U is N or CH:


8. The compound of any claim 1 wherein L is a covalent bond, —CH₂—, or—(C═O)—.
 9. The compound of claim 8 wherein G is chosen from hydrogen,hydroxy, N-methylethanolamino, —N(C₁-C₆ alkyl)₂, optionally substitutedmorpholin-4-yl, optionally substituted piperazin-1-yl, optionallysubstituted piperazin-2-yl, optionally substituted homopiperazin-1-yl,and optionally substituted cyclopropyl.
 10. The compound of claim 1wherein chosen fromN-{3-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4S,7R)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-({4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]phenyl}amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-(4R,7S)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,4-difluorophenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-fluoro-6-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;(4S,7R)—N-[3-fluoro-6-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(+) isomer;(4R,7S)—N-[3-fluoro-6-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(−) isomer;N-(5-(6-(4-(4-(dimethylamino)piperidin-1-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2,4-difluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-methyl-4-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-chloro-4-methyl-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-fluoro-6-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(4-fluoro-2-methyl-3-(6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-fluoro-6-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;(4R,7S)—N-[2-fluoro-5-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(−) isomer;(4S,7R)—N-[2-fluoro-5-(1-methyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide(+) isomer;N-(2,6-difluoro-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-fluoro-2-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-chloro-6-methyl-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-fluoro-6-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-fluoro-2-methyl-3-(5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-chloro-3-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-(6-(1-ethyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2,6-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-fluoro-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-chloro-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-3-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-(6-(1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-5-fluoropyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(1-methylpiperidin-4-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2,6-difluoro-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-fluoro-2-methyl-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-chloro-6-methyl-3-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-fluoro-6-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-fluoro-6-(1-methyl-5-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2,6-difluoro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(6-fluoro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-chloro-3-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(3-fluoro-6-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(5-fluoro-6-(6-(4-((isopropyl(methyl)amino)methyl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)pyridin-2-yl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-{2-methyl-3-[4-methyl-6-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5-oxo-4,5-dihydropyrazin-2-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;3-fluoro-N-[2-methyl-3-(4-methyl-6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{5-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3-yl}-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-methyl-3-(1-methyl-5-{[5-(morpholin-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-(5-(5-((isopropyl(methyl)amino)methyl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-[2-methyl-3-(1-methyl-5-{[6-(morpholin-4-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[5-({5-[4-(dimethylamino)piperidin-1-yl]pyridin-2-yl}amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]-2-methylphenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-methyl-3-(1-methyl-5-{[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[5-(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{2-methyl-3-[1-methyl-6-oxo-5-({5-[4-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)-1,6-dihydropyridin-3-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-methyl-3-(5-{[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{2-methyl-3-[1-methyl-6-oxo-5-({6-[4-(propan-2-yl)piperazin-1-yl]pyridazin-3-yl}amino)-1,6-dihydropyridin-3-yl]phenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[6-(4-ethylpiperazin-1-yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(3-{6-[(4-{[(2-hydroxyethyl)(methyl)amino]methyl}phenyl)amino]-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl}-2-methylphenyl)-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[6-(4-hydroxy-4-methylpiperidin-1-yl)pyridazin-3-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-methyl-3-(1-methyl-5-{[5(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[2-methyl-3-(1-methyl-5-{[5(1,4-oxazepan-4-yl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-{3-[6-(1H-indazol-5-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl]-2-methylphenyl}-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-[3-(5-{[5(4-ethylpiperazin-1-yl)pyridin-2-yl]amino}-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-methylphenyl]-4,7-methano-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;N-(2-fluoro-5-(8-(4-(4-methylpiperazin-1-yl)phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-yl)phenyl)-4,7-methano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,6-ethano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiazole-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-4,7-ethano-4,5,6,7-tetrahydrobenzo[b]thiazole-2-carboxamide;N-(2-fluoro-5-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide;N-(2-fluoro-5-(4-methyl-6-(4-(4-methylpiperazin-1-yl)phenylamino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-5,8-ethano-5,6,7,8-tetrahydronaphthalene-2-carboxamide;and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, prodrugs, and mixtures thereof.
 11. A pharmaceuticalcomposition, comprising a compound of claim 1, together with at leastone pharmaceutically acceptable vehicle chosen from carriers, adjuvants,and excipients.
 12. A pharmaceutical composition of claim 11, whereinthe composition is formulated in a form chosen from injectable fluids,aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmicsolutions, and transdermal patches.
 13. A packaged pharmaceuticalcomposition, comprising a pharmaceutical composition of claim 11; andinstructions for using the composition to treat a patient suffering froma disease responsive to inhibition of Btk activity.
 14. The packagedpharmaceutical composition of claim 13 wherein the disease responsive toinhibition of Btk activity is cancer.
 15. The packaged pharmaceuticalcomposition of claim 13 wherein the disease responsive to inhibition ofBtk activity is chosen from bone disorders, allergic disorders,autoimmune diseases, inflammatory diseases, and acute inflammatoryreactions.
 16. A method for treating a patient having a diseaseresponsive to inhibition of Btk activity, comprising administering tothe patient an effective amount of a compound of claim
 1. 17. The methodof claim 16 wherein the patient is a human.
 18. The method of claim 16wherein the patient is chosen from cats and dogs.
 19. The method ofclaim 16 wherein the disease responsive to inhibition of Btk activity iscancer.
 20. The method of claim 19 wherein the disease responsive toinhibition of Btk activity is B-cell lymphoma and leukemia.
 21. Themethod of claim 16 wherein an effective amount of said compound isadministered by a method chosen from intravenously, intramuscularly, andparenterally.
 22. The method of claim 16 wherein an effective amount ofsaid compound is administered orally.
 23. A method for treating apatient having a disease chosen from cancer, bone disorders, autoimmunediseases, inflammatory diseases, acute inflammatory reactions, andallergic disorders comprising administering to the patient an effectiveamount of a compound of claim
 1. 24. The method of claim 23 wherein thepatient is a human.
 25. The method of claim 23 wherein the patient ischosen from cats and dogs.
 26. The method of claim 23 wherein aneffective amount of said compound is administered by a method chosenfrom intravenously, intramuscularly, and parenterally.
 27. The method ofclaim 23 wherein an effective amount of said compound is administeredorally.
 28. A method for increasing sensitivity of cancer cells tochemotherapy, comprising administering to a patient undergoingchemotherapy with a chemotherapeutic agent an amount of a compound ofclaim 1 sufficient to increase the sensitivity of cancer cells to thechemotherapeutic agent.
 29. A method of reducing medication error andenhancing therapeutic compliance of a patient being treated for adisease responsive to inhibition of Btk activity, the method comprisingproviding a packaged pharmaceutical preparation of claim 13 wherein theinstructions additionally include contraindication and adverse reactioninformation pertaining to the packaged pharmaceutical composition.
 30. Amethod for inhibiting ATP hydrolysis, the method comprising contactingcells expressing Btk with a compound of claim 1 in an amount sufficientto detectably decrease the level of ATP hydrolysis in vitro.
 31. Themethod of claim 30 wherein the cells are present in a mammal.
 32. Themethod of claim 31 wherein the mammal is a human.
 33. The method ofclaim 31 wherein the mammal is chosen from cats and dogs.
 34. A methodfor determining the presence of Btk in a sample, comprising contactingthe sample with a compound of claim 1 under conditions that permitdetection of Btk activity, detecting a level of Btk activity in thesample, and therefrom determining the presence or absence of Btk in thesample.
 35. A method for inhibiting B-cell activity comprisingcontacting cells expressing Btk with a compound of claim 1, in an amountsufficient to detectably decrease B-cell activity in vitro.